- T-wave alternans (TWA) refers to beat-to-beat variability in the T-wave morphology and amplitude on ECGs and reflects temporal heterogeneity in ventricular repolarization, an important mechanism for arrhythmias. - TWA can be measured using frequency or time domain analyses and has been associated with increased risk of sudden cardiac death and mortality in various populations, though limitations exist. - TWA testing can yield positive, negative, or indeterminate results but its use in guiding therapy such as ICD implantation requires further evidence.

1. Micro T wave alternans
Dr. Yogesh Shilimkar

2. • Microvolt T-wave alternans (TWA)
– characterised as beat-to-beat fluctuation of T-wave
amplitude and morphology,
– is an electrophysiological phenomenon associated
clinically with impending ventricular arrhythmias
– is an important marker of arrhythmia risk.
– associated with cardiovascular mortality and sudden
cardiac death

3. Physiological Bases of T-wave
Alternans

4. • It reflects spatiotemporal heterogeneity of
repolarisation.
• It results from beat-to-beat alterations in intracellular
calcium handling, which is reflected in the shape and
duration of the action potential at the level of cardiac
myocytes.
• These local differences in the repolarisation of the
neighbouring myocardial regions can ultimately
predispose the individual to lethal arrhythmias such as
ventricular tachycardia or ventricular fibrillation.

6. • It arises from beat-to-beat alternation of
action potential duration at the level of
cardiac myocytes.
• TWA can be either
– spatially concordant, when action potentials in
neighboring cell regions alternate in phase, or
– discordant, when they are out of phase

7. Discordant Alternans Leading to VF
Action potential propagation between 2 ventricular sites (A to B) is shown
with transition from concordant to discordant alternans and development
of ventricular fibrillation (VF).
Shaded areas indicate dispersion of repolarization between sites.
*Premature beats. L = long action potential duration; S = short action
potential duration.

8. Hypotheses to explain TWA
• Tissue heterogeneity –
– According to this hypothesis, dispersion of repolarization results
in differences in electrical recovery time and conduction among
myocytes .
– Longer recovery time, or delayed activation time, in some
myocytes may alter their depolarization from beat-to-beat.
• Dynamic functional tissue factors –
– TWA may be due to dynamic functional tissue factors. These
include the rate-dynamics (restitution) of repolarization and
conduction velocity.
• Mechanical and ionic abnormalities –
– Acute volume overload exaggerates TWA, suggesting a role for
mechanical stretch.
– At the ionic level, abnormal calcium cycling is emphasized in the
etiology of TWA, and may underscore the prevalence of TWA in
patients with heart failure and cytosolic calcium loading

10. • Conditions that amplify TWA
– increased heart rate,
– ventricular premature beats,
– coronary ischaemia and
– adrenergic stimulation
• Interventions diminish TWA:
– b-blockers,
– sympathetic denervation
– vagus nerve stimulation

11. T-wave Alternans Analysis Techniques
• Two of the most widely used TWA analysis
techniques in clinical studies are
– the spectral method and
– the modified moving average (MMA) method.
• Both of these methods perform similarly in
terms of risk prediction, but there are
significant differences in their implementation
and interpretation.

12. Spectral method
• It requires the patient to achieve a target heart rate of 105–
110 beats per minute for a period of time using a
specialised exercise protocol, pharmacological agents or
atrial pacing.
• This method requires the use of proprietary high-resolution
electrodes.
• In the spectral method, a composite power spectrum of the
ST–T segment amplitude fluctuations is formed by applying
fast Fourier transform technique to the beat-to-beat series
of amplitude measurements along the JT-interval in 128
consecutive QRS-aligned ECG complexes.

14. • The alternans voltage is defined as the square root of the spectral
power occurring at the alternans frequency (0.5 cycles/beat) after
noise reduction.
• It corresponds to the difference in voltage between the overall
average beat and either the averaged even or odd-numbered beat
(i.e. half of the difference between the averaged even and odd
beats).
• A TWA level ≥1.9 μV with sufficient signal-to-noise ratio for >2 min
is defined as a positive test result, while a TWA level <1.9 μV is
considered negative.
• However, as the spectral method requires a stable target heart rate
to be achieved, a relatively large proportion (approximately 20–40
%) of tests are classified as ‘indeterminate’, either due to patient-
related factors such as failure to achieve the target heart rate,
excessive ventricular ectopy, atrial fibrillation or unsustained TWA,
or technical problems such as noise in the recording.

15. Modified Moving Average (MMA) method
• The is time-domain based, and employs recursive
averaging.
• The algorithm continuously streams odd and even beats
into separate bins and creates averaged complexes for both
bins.
• These complexes are then superimposed, and the
maximum difference between the odd and even complexes
at any point within the JT-segment is averaged for every 10
or 15 seconds and reported as the TWA value.
• The MMA method allows TWA analysis during routine
exercise stress testing and also during 24-hour ambulatory
ECG monitoring.

17. • No special electrodes are required using this
technique, and as no target heart rate is
required, indeterminate results are infrequent
with the MMA method.
• Risk stratification is based on the peak TWA
value using the MMA, and cut-off levels are
– Abnormal TWA: ≥47 μV and
– severely abnormal TWA: ≥60 μV.

18. Modification of T-wave Alterans

19. • Pharmacological therapy with b-blockers significantly reduces
the level of TWA, and can convert a positive test to negative in
approximately in half of the cases.
• It is reasonable to assume, that while b-blockers may alter the
development of TWA, they may similarly modulate
susceptibility to ventricular arrhythmias.
• In a meta-analysis among patients with LV dysfunction on
continuous b-blocker therapy, abnormal TWA testing was
associated with a fivefold risk of ventricular arrhythmic
events, whereas only weak association was noted in studies
on which b-blocker therapy was withheld prior to screening.
• Consequently, any TWA testing is suggested to be performed
under continuous medical therapy.

20. • TWA may also detect influences of non-
pharmacological interventions that are known to be
associated with reduced mortality rates as well.
• In patients with stable coronary artery disease, exercise
rehabilitation reduced TWA levels in both patients with
and without diabetes, and during the 2-year follow-up
a large proportion of the patients with positive TWA
converted to negative TWA.
• Thus, TWA seems to be a method that may capture and
quantify influence of mainstream clinical interventions
to arrhythmia susceptibility.

21. Prognostic Significance of T-wave Alternans
• Microvolt TWA has been associated with cardiovascular mortality and SCD in
individuals with both ischaemic and non-ischaemic cardiomyopathy, and with
reduced as well as preserved left ventricular function.
• These prognostic implications were independent from several demographic
and clinical factors associated with coronary artery disease and SCD, including
LVEF.
• The spectral method has demonstrated TWA to be predictive of future
cardiovascular events in patients with ischaemic heart disease and prior MI, &
in non-ischaemic cardiomyopathy and heart failure.
• Indeterminate test results have been shown to predict mortality at least as
well as positive tests, thus positive and indeterminate test results are often
pooled together as ‘non-negative’ TWA, and compared with negative TWA.
• In some studies, the spectral method has failed to demonstrated significant
association between TWA and SCD or mortality. These negative results are at
least partly due to discontinuation of b-blocker therapy before the test, TWA
testing shortly after occurrence of MI during ongoing remodelling and using
ICD discharge as the endpoint.

22. • The prognostic significance of the MMA method has been
demonstrated in patients with reduced and preserved LVEF,
including those with coronary artery disease and prior MI.
• To date, the largest study on TWA is the Finnish
Cardiovascular Study (FINCAVAS) with nearly 3,600 patients
with generally preserved left ventricular function referred
to routine exercise testing and analysed using the MMA
method.
• TWA was demonstrated to be associated with increased
cardiovascular mortality and SCD rates, with higher TWA
values indicating greater risk.
• In a meta-analysis on TWA in the setting of ambulatory
ECG, the group with positive TWA had over a sevenfold risk
of SCD compared with those with negative TWA.

23. Role of T-wave Alternans Testing to
Guide Therapy in Clinical Practice

24. Microvolt T-Wave Alternans Assessment in Patients
With Impaired Left Ventricular Function
• Only a minority of patients qualifying for prophylactic ICD based on
reduced LVEF ≤35 % receive appropriate therapies from the device.
• Many TWA studies have tried to distinguish patients who are likely
to benefit from ICD therapy from those that are not.
• In patients with EF ≤35 % but no ICD therapy, negative TWA was
associated with a low incidence of SCD, compared with substantial
SCD risk associated with both positive TWA and indeterminate
TWA.
• In patients with ischaemic cardiomyopathy, ICDs were associated
with lower all-cause mortality rate in patients with non-negative
TWA, but not in patients with negative TWA.

25. • In the Microvolt T Wave Alternans Testing for Risk
Stratification of Post MI Patients (MASTER I) study,
which enrolled MADIT-II type ICD-patients with
LVEF ≤30 %, risk of ventricular arrhythmias did not
differ according to TWA classification, despite
differences in total mortality rates.
• Similar results have been reported from a SCD-HeFT
ICD-study,
– TWA could not predict arrhythmic events or mortality.
– These results have been partly attributed to the use of
ICD discharge as an endpoint, which may have
underestimated the use of TWA.

26. Microvolt T-Wave Alternans Assessment and
Results of Invasive Electrophysiological Testing
• The ABCD (Alternans Before Cardioverter
Defibrillator) trial tested whether TWA can guide
ICD therapy in patients with ischaemic
cardiomyopathy and non-sustained ventricular
tachycardia.
– Event rates were over twofold higher both among
patients with positive TWA and positive
electrophysiological study at the pre-specified 1-year
endpoint.
– However, TWA did not predict endpoint events at 2
years.

27. Microvolt T-Wave Alternans Assessment in
Patients After Myocardial Infarction
• According to the REFINE (Risk Estimation Following
Infarction Noninvasive Evaluation) study,
– TWA testing should be performed only 10 to 14 weeks
after an MI, as TWA testing in the early recovery period did
not reliably identify patients at long-term risk of cardiac
death.
– It should be performed on permanent medication, as
halting b-blocker medication prior to TWA affects the
results and does not reflect the long-lasting circumstances.
– Repeated annual testing has been also suggested, as an
individual’s vulnerability to ventricular arrhythmias may
change over time

28. Predicting inducible VT/VF at
electrophysiology study
• Initial studies of TWA used inducible VT and VF as
surrogate endpoints for arrhythmic risk. These
studies demonstrated that the presence of TWA
during atrial or ventricular pacing or exercise
correlated with the ability to induce ventricular
arrhythmias in patients undergoing EP testing.
• Abnormal TWA results have been associated with
relatively high sensitivity and specificity (both
between 75 and 85 percent) for the prediction of
inducible VT or VF during invasive EP testing.

29. Long QT syndrome
• Microvolt TWA is much more common in LQT syndromes, occurring
in 44 percent of patients.
• The mechanism of TWA in LQTS patients may differ from that in
patients with CAD, and the following mechanisms have been
proposed:
– LQTS-associated TWA may represent early after depolarizations during
phase 2 or phase 3 of the action potential that occur in alternate beats
due to alternation in the duration of the plateau (phase 2) associated
with increased susceptibility to this type of electrical instability.
– In a canine model of LQTS, TWA was induced by abrupt increases in
heart rate. This was accompanied by significant increases in the
dispersion of repolarization between epicardial and midmyocardial
regions compared with baseline. A similar mechanism has been
observed in patients with congenital LQTS following abrupt heart rate
acceleration, in which it was shown that successive beats may
encroach upon refractoriness resulting from repolarization dispersion
to cause functional conduction block and reentry.

30. • An expert consensus statement by the American Heart
Association/American College of Cardiology
Foundation on risk stratification techniques on SCD in
2008 asserted that
– TWA may be useful for SCD risk stratification, but further
information is needed on how to implement this test in
clinical practice.
• Similar recommendations were provided in a
consensus document focusing specifically on TWA in
2011.
– The paper concluded that it is reasonable to consider TWA
evaluation when there is suspicion of vulnerability to lethal
arrhythmias, but also acknowledged that there is not
sufficient evidence from interventional trials to suggest
that TWA can be used to guide therapy.

31. • However, the recent European Society of
Cardiology guidelines for the management of
patients with ventricular arrhythmias and the
prevention of sudden cardiac death made no
recommendations for the use of TWA in risk
assessment
• Although abnormal TWA clearly has prognostic
implications, and positive or non-negative tests
have been associated with substantially increased
risk, currently there is not enough evidence to
recommend that TWA should be used to guide
therapy, such as ICD implantation.

32. SUMMARY

33. • T-wave alternans (TWA) refers to periodic beat-to-beat variability in
the timing, shape, and/or amplitude of T-waves on the surface
electrocardiogram (ECG). TWA therefore reflects abrupt temporal
heterogeneity in ventricular repolarization, which is an important
mechanism underlying reentrant arrhythmias.
• TWA reflects periodic changes in temporal heterogeneity or dispersion
in ventricular repolarization, which is an important mechanism
underlying reentrant arrhythmias. Thus, TWA is a noninvasive method
for assessing risk for sudden cardiac arrest using the surface ECG.
• While historically detected by visual inspection of the surface ECG,
TWA can now be measured using commercial systems that use
frequency or time domain analyses.
• All methods for T-wave alternans detection have some limitations but
have been validated empirically in different populations. Future
advances may come from methods that analyze other aspects of
repolarization variability including non-alternating periodicity and
regional variations in T-wave oscillations.
• TWA testing may yield positive (abnormal), negative (normal), or
indeterminate results.